The cause is not known in 90% to 95% of cases.[5] The remaining 5–10% of cases are inherited from a person's parents.[4] About half of these genetic cases are due to one of two specific genes.[5] The diagnosis is based on a person's signs and symptoms, with testing done to rule out other potential causes.[5]

No cure for ALS is known.[5] A medication called riluzole may extend life by about two to three months.[7]Non-invasive ventilation may result in both improved quality and length of life.[6] The disease can affect people of any age, but usually starts around the age of 60 and in inherited cases around the age of 50.[4] The average survival from onset to death is two to four years.[9] About 10% survive longer than 10 years.[5] Most die from respiratory failure.[4] In much of the world, rates of ALS are unknown.[4] In Europe and the United States the disease affects about two to three people per 100,000 per year.[4][12][10]

Descriptions of the disease date back to at least 1824 by Charles Bell.[13] In 1869, the connection between the symptoms and the underlying neurological problems was first described by Jean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis.[13] It became well known in the United States in the 20th century when in 1939 it affected the baseball player Lou Gehrig and later worldwide following the 1963 diagnosis of cosmologistStephen Hawking.[14][15] In 2014, videos of the Ice Bucket Challenge went viral on the Internet and increased public awareness of the condition.[16]

ALS itself can be classified a few different ways: by how fast the disease progresses (slow vs fast progressors), by whether it is inherited or sporadic, and by where it starts.[5] Most commonly (~70% of the time) the limbs are affected first. In this case, neurons in the brain (upper motor neurons) and in the spinal cord (lower motor neurons) are dying and this form is called "limb onset". In about 25% of cases, muscles in the face, mouth, and throat are affected first, because motor neurons in the part of the brain stem called the medulla oblongata (formerly called the "bulb") start to die first along with lower motor neurons. This form is called "bulbar onset". In about 5% of cases muscles in the trunk of the body are affected first. In all cases the disease spreads and affects other regions.[4] The symptoms may also be limited to one spinal region.

Those with leg amyotrophic diplegia and brachial amyotrophic diplegia have a longer survival compared to classic onset ALS.[17]

The disorder causes muscle weakness and atrophy throughout the body due to the degeneration of the upper motor and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel function and the muscles responsible for eye movement are usually spared until the final stages of the disorder.[9]

The start of ALS may be so subtle that the symptoms are overlooked.[5] The earliest symptoms of ALS are muscle weakness or muscle atrophy. Other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first.[21]

In limb-onset ALS, people first experience awkwardness when walking or running or even tripping over or stumbling may be experienced and often this is marked by walking with a "dropped foot" which drags gently on the ground. Or if arm-onset, difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock may be experienced.[21]

In bulbar-onset ALS, initial symptoms will mainly be of difficulty speaking clearly or swallowing. Speech may become slurred, nasal in character, or quieter. There may be difficulty in swallowing and loss of tongue mobility. A smaller proportion of people experience "respiratory-onset" ALS, where the intercostal muscles that support breathing are affected first.[4]

Over time, people experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations) although twitching is not a diagnostic symptom and more of a side effect so twitching would either occur after or accompany weakness and atrophy.[5]

Although the order and rate of symptoms vary from person to person, the disease eventually spreads to unaffected regions and the affected regions become more affected. Most people eventually are not able to walk or use their hands and arms, lose the ability to speak and swallow food and their own saliva, and begin to lose the ability to cough and to breathe on their own.[9]

The rate of progression can be measured using an outcome measure called the "ALS Functional Rating Scale Revised (ALSFRS-R)", a 12-item instrument administered as a clinical interview or self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability);[22] it is the most commonly used outcome measure in clinical trials and is used by doctors to track disease progression.[23] Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, people with ALS lose about 0.9 FRS points per month. A survey-based study amongst clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful.[24]

Disorder progression tends to be slower in people who are younger than 40 at onset,[25] are mildly obese,[26] have disorder restricted primarily to one limb, and those with primarily upper motor neuron symptoms.[27] Conversely, progression is faster and prognosis poorer in people with bulbar-onset disorder, respiratory-onset disorder, and frontotemporal dementia.[27]

The CX3CR1allelic variants have also been shown to have an effect on the disorder's progression and life expectancy.[28]

Difficulty in chewing and swallowing makes eating very difficult and increases the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung function such as vital capacity and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. Most people with ALS die of respiratory failure or pneumonia.[4]

Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die between two and four years after the diagnosis.[9] Around half of people with ALS die within 30 months of their symptoms beginning, and about 20% of people with ALS live between 5 years and 10 years after symptoms begin.[4] Guitarist Jason Becker has lived since 1989 with the disorder, while cosmologistStephen Hawking lived for 55 more years following his diagnosis, but they are considered unusual cases.[29]

Most people with ALS die in their own home, with their breath stopping while they sleep; people rarely choke to death.[11]

About 5–10% of cases are directly inherited from a person's parents.[4] Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS.[30][31]

A defect on chromosome 21, which codes for superoxide dismutase, is associated with about 20% of familial cases of ALS, or about 2% of ALS cases overall.[32][33][34] This mutation is believed to be transmitted in an autosomal dominant manner, and has over a hundred different forms of mutation. The most common ALS-causing mutation is a mutant SOD1 gene, seen in North America; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS, and people with this form of the disorder survive for an average of 11 years.[35][medical citation needed]

In 2011, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9orf72, which is associated with ALS combined with frontotemporal dementia (ALS-FTD),[36] and accounts for some 6% of cases of ALS among white Europeans.[37]

In 1994 the National Institute for Occupational Safety and Health (NIOSH) reported a nonsignificant increase in nervous system disorders due to four cases of ALS among National Football League (NFL) players. It was unclear if this was due to chance or not.[40] Another study from 2012 also found a possible increase in ALS in NFL football players.[41] An older study did not find an increased risk among high school football players.[38] A 2007 review found an increased risk among soccer players.[39] ALS may also occur more often among the US military veterans however the reason is unknown.[42] This may be due to head injury.[43]

After the 2012 report was released, some NFL players involved in the legal settlement with the NFL complained that the NFL, which initially agreed to pay $765 million, was not doing enough to help players. The judge in the case concurred, and the NFL then agreed to pay an unlimited amount of damages for players found to have ALS, Parkinson's disease, Alzheimer's disease and dementia.[44]

Where no family history of the disease is present — around 90% of cases — no cause is known. Possible associations for which evidence is inconclusive include military service and smoking.[18] Although studies on military history and ALS frequency are inconsistent, there is weak evidence for a positive correlation.[45] Various proposed factors include exposure to environmental toxins (inferred from geographical deployment studies), as well as alcohol and tobacco use during military service.[45]

The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop protein-rich inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation.[52] These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), or FUS.[53] The mutant SOD1 may also contribute to motor neuron cell death through generating free radicals.[54]

Excitotoxicity, or cell death caused by high levels of intracellular calcium caused by excessive activity of excitatory neurotransmitters, may be a mechanism of ALS. This concept has been supported by increased glutamate and dysfunctional glutamate transporter–RNA in cerebrospinal fluid of those with ALS.[3] This is further supported by the only effective treatment being an anti-glutaminergic drug (Riluzole), as well as the poor ability to buffer calcium in motor neurons relative to other neurons.[55]

Neurofilament accumulation in axons has been observed in sporadic cases of ALS, as well as in SOD1 patients, possibly interfering with axonal transport, leading to cell death from SOD1 toxicity.[56]

No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive.[5] Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the person and a series of tests to rule out other diseases.[5] Physicians obtain the person's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are worsening.[5] A number of biomarkers are being studied for the condition, but so far are not in general medical use.[57][58]

Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions.[5] One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles.[5] Certain EMG findings can support the diagnosis of ALS.[5] Another common test measures nerve conduction velocity (NCV).[5] Specific abnormalities in the NCV results may suggest, for example, that the person has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. While a magnetic resonance imaging (MRI) is often normal in people with early stage ALS, it can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical spondylosis.[5]

Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests.[5] In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.[5]

ALS must be differentiated from the "ALS mimic syndromes" which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants.[62] Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, people with ALS symptoms should always obtain a specialist neurological opinion in order to rule out alternative diagnoses. Myasthenic syndrome, also known as Lambert–Eaton syndrome, can mimic ALS, and its initial presentation can be similar to that of myasthenia gravis (MG), a treatable autoimmune disease sometimes mistaken for ALS.[63][64]Benign fasciculation syndrome is another condition that mimics some of the early symptoms of ALS, but is accompanied by normal EMG readings and no major disablement.[65]

Most cases of ALS, however, are correctly diagnosed, with the error rate of diagnosis in large ALS clinics is less than 10%.[66][67] One study examined 190 people who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these people (16%) had their diagnosis completely changed during the clinical observation development period.[68] In the same study, three people had a false negative diagnosis of MG, which can mimic ALS and other neurological disorders, leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.[69]

Management of ALS attempts to relieve symptoms and extend life expectancy. This supportive care is best provided by multidisciplinary teams of healthcare professionals working with the person and their caregivers to keep them as mobile and comfortable as possible.[citation needed]

Riluzole has been found to modestly prolong survival by approximately two to three months.[70][7] It may have a greater survival benefit for those with a bulbar onset.[7] It is approved by the United States Food and Drug Administration (FDA) and recommended by the National Institute for Health and Care Excellence (NICE) in England ad Wales). Riluzole does not reverse damage already done to motor neurons,[71] but affects neurons by reducing their activity through blocking Na+ entrance into the neurons and thus blocking the release of the chemicals that causes the activity of the motor neurons.[72] The reduction in activity prevents the ruining of the neuronal muscle and so the drug can act as a protective chemical.[72] Studies have shown that the function of this drug is dependent on the amount taken at a given time. The higher the concentration, the better the drug will protect the neurons from ruin.[72] The recommended dosage of Riluzole is 50 mg, twice a day for people with known ALS for more than five years.[3]

There are a number of side effects caused by the drug including the feeling of weakness in muscles, but this is normal due to the function of the drug.[72] Studies have shown that people on the drug are not likely to stop responding to it or develop symptoms that might cause the activity of neurons to rise again, making Riluzole an effective drug for prolonging survival.[73]

In 2015, edaravone was approved in Japan for treatment of ALS after studying how and whether it works on 137 people with ALS[74] and has obtained orphan drug status in the European Union and United States.[75] On May 5, 2017, the FDA approved edaravone to extend the survival period of people with ALS.[8] It costs about US$145,000 per year in the United States and US$35,000 per year in Japan.[76]

Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Drugs also are available to help people with pain, such as non-steroidal and anti-inflammatory drugs and opioids,[77] depression, sleep disturbances, dysphagia, and constipation. Baclofen and diazepam are often prescribed to control the spasticity caused by ALS, and trihexyphenidyl, amitriptyline or most commonly glycopyrrolate[3] may be prescribed when people with ALS begin having trouble swallowing their saliva.[9] There is no evidence that medications are effective at reducing muscle cramps experienced by people with ALS.[78]

Respiratory failure is the most common cause of death in people with ALS and is the most prominent symptom, second to the destruction of motor neurons and weakening of muscle.[3] When the muscles that assist in breathing weaken, several symptoms start to arise including shortness of breath when undergoing physical activity or talking, fatigue, morning headaches, poor concentration and depression.[3] The use of ventilatory assistance (intermittent positive pressure ventilation, bilevel positive airway pressure (BiPAP), or biphasic cuirass ventilation (BCV) may be used to aid breathing. Such devices artificially inflate the person's lungs from various external sources that are applied directly to the face or body. When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time. BCV has the added advantage of being able to assist in clearing secretions by using high-frequency oscillations followed by several positive expiratory breaths.[79] People may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as a tracheotomy, in which a plastic breathing tube is inserted directly in the person's windpipe through an opening in the neck.[citation needed]

Persons and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the person's quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. People need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support and have deep discussions on quality of life. Some persons under long-term tracheostomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheostomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough, though in all cases speech will be lost as the disease progresses. This technique preserves speech in some persons with long-term mechanical ventilation. Other persons may be able to use a speaking valve such as a Passey-Muir speaking valve with the assistance and guidance of a speech-language pathologist.[citation needed]

External ventilation machines that use the ventilation mode of BiPAP are frequently used to treat respiratory insufficiency at night, and later during the daytime.[3] The use of BPAP (more often referred to as noninvasive ventilation, NIV) has shown to prolong survival and slow down the progression of forced vital capacity,[3] but long before BPAP stops being effective, persons should decide whether to have a tracheotomy and long-term mechanical ventilation. At this point, some persons choose palliative hospice care.[citation needed]

Using low tech to communicate. A man with ALS communicates by pointing to letters and words using a head mounted laser pointer.

Physical therapy plays a large role in rehabilitation for individuals with ALS. Specifically, physical, occupational, and speech therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, improving speech and swallowing, preventing complications, and promoting functional independence.[80][81]

Occupational therapy and special equipment such as assistive technology can also enhance people's independence and safety throughout the course of ALS.[82] Gentle, low-impact aerobic exercise such as performing activities of daily living, walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles, because muscle exhaustion can lead to worsening of symptoms associated with ALS, rather than providing help to people with ALS.[77] They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help people remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable ALS people to retain as much safety and independence in activities of daily living as possible.[82]

People with ALS who have difficulty speaking may benefit from working with a speech-language pathologist.[81] These health professionals can teach people adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) or low-tech communication techniques such as head mounted laser pointers, alphabet boards or yes/no signals.[81]

People with ALS and caregivers can learn from dieticians how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber and fluid, and how to avoid foods that are difficult to swallow. Providing meals with vitamin E and taking vitamin E supplements have shown to slow down the progression of ALS.[3] People may begin using suction devices to remove excess fluids or saliva and prevent choking. Occupational therapists can assist with recommendations for adaptive equipment to ease the physical task of self-feeding. Speech-language pathologists make food choice recommendations that are more conducive to their unique deficits and abilities. When people with ALS can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does not prevent people from eating food orally if they wish.[citation needed]

Researchers have stated, "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake"[83] and have a severe loss of appetite.[84] Both animal[85] and human research[83][unreliable medical source?][86][unreliable medical source?] suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their caloric intake. As of 2012, "a lack of robust evidence for interventions" remained for the management of weight loss.[87]

Social workers and home care and hospice nurses help people with ALS, their families, and caregivers with the medical, emotional, and financial challenges of coping, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney, preparing a living will, and finding support groups for patients and caregivers. Home nurses are available not only to provide medical care, but also to teach caregivers about tasks such as maintaining respirators, giving feedings, and moving people to avoid painful skin problems and contractures. Home hospice nurses work in consultation with physicians to ensure proper medication, pain control, and other care affecting the quality of life of people with ALS who wish to remain at home. The home hospice team can also counsel people with ALS and caregivers about end-of-life issues.[citation needed]

In much of the world, rates of ALS are unknown.[4] In Europe, the disease affects about 2.6 people per 100,000 per year.[10] In the United States, more than 5,600 are diagnosed every year (over 1.5 per 100,000 per year), and up to 30,000 Americans are currently affected. ALS is responsible for two deaths per 100,000 Americans per year.[88][89][90]

ALS is classified as a rare disease designated by the FDA as an "orphan" disease (affecting fewer than 200,000 people in the United States), but is the most common motor neuron disease. One or two of 100,000 people develop ALS each year.[91] ALS cases are estimated at 1.2–4.0 per 100,000 individuals in Caucasian populations with a lower rate in other ethnic populations.[92] People of all races and ethnic backgrounds may be affected. Filipinos are second to Caucasians in terms of ALS prevalence, with 1.1-2.8 per 100,000 individuals.[89] The disease can affect people at any age, but usually starts around the ages of 58 to 63 years for sporadic disease and 47 to 52 years for familial disease.[4][18]

English scientist Augustus Waller described the appearance of shriveled nerve fibers in 1850. In 1869, the connection between the symptoms and the underlying neurological problems were first described by Jean-Martin Charcot, who initially introduced the term amyotrophic lateral sclerosis in his 1874 paper.[13] In 1881, the article was translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System.

ALS became a cause célèbre in the United States in 1939 when baseball legend Lou Gehrig's career, and two years later, his life, were ended by the disease.[93]

By 1991, researchers had linked chromosome 21 to familial ALS (FALS). In 1993, the SOD1 gene on chromosome 21 was found to play a role in some cases of FALS. In 1996, riluzole became the first FDA-approved drug for ALS.[citation needed]

In 1998, the El Escorial criteria were developed as the standard for classifying people with ALS in clinical research. The next year, the revised ALS Functional Rating Scale was published and soon becomes a gold standard for clinical research. Noncoding repeat expansions in C9ORF72 were found to be a major cause of ALS and frontotemporal dementia in 2011.[citation needed]

In August 2014, a challenge went viral online, commonly known as the "ALS Ice Bucket Challenge".[95] Contestants fill a bucket full of ice and water, then state who nominated them to do the challenge, and nominate three other individuals of their choice to take part in it. The contestants then dump the buckets of ice and water onto themselves. However, it can be done in a different order. The contestants then donate at least US$10 (or a similar amount in their local currency) to ALS research at the ALS Association, the ALS Therapy Development Institute, ALS Society of Canada or Motor Neurone Disease Association in the UK. Any contestants who refuse to have the ice and water dumped on them are expected to donate at least US$100 to ALS research. As of July 2015[update], the Ice Bucket Challenge had raised $115 million for the ALS Association.[96] Many celebrities have taken part in the challenge.[97] The Ice Bucket Challenge was credited with helping to raise funds that contributed to the discovery that the gene NEK1 may potentially contribute to the development for ALS.[98][99]

Repetitive transcranial magnetic stimulation had been studied in ALS in small and poorly designed clinical trials; as of 2013, there was insufficient evidence to know whether rTMS is safe or effective for ALS.[100]

One 2016 review of stem-cell therapy trials found tentative evidence that intraspinal stem cell implantation was relatively safe and possibly effective.[101] A 2016 Cochrane review of cell based therapies found that there was insufficient evidence to speculate about efficacy.[102] Stem cell therapy can provide additional proteins and enzymes that have shown to help prolong survival and control the symptoms associated with ALS.[77][103] Those proteins include neurotrophic factors and insulin-like growth factor 1. Both those proteins are still under clinical trials and need to be further studied to evaluate their efficiency and associated side effects.[77][103]

^ ab"FDA approves drug to treat ALS". U.S. Food and Drug Administration. 5 May 2017. Archived from the original on 8 May 2017. The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo

^ abcdBellingham MC (2011). "A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade?". CNS Neuroscience and Therapeutics. 1 7 (1): 4–31. doi:10.1111/j.1755-5949.2009.00116.x. PMID20236142.